PROJECT SUMMARY/ABSTRACT: P3. Targeting MYC Recurring genetic perturbations in colorectal cancer (CRC) activate MYC, an oncogenic transcription factor that features prominently in human cancer. Despite the pervasive involvement of MYC in CRC, and a wealth of studies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse model systems, MYC is generally considered undruggable. Indeed, there are currently no drug-like molecules capable of directly blocking MYC function in cancer cells. Recently, however, we presented a new paradigm for target gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function. We found that the stable association of MYC with chromatin depends on its direct interaction with the chromatin scaffolding protein WDR5, which co-localizes broadly with MYC across the genome and facilitates MYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallow, hydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is to target the MYC?WDR5 interface to discover a drug that will disable MYC function in CRC by preventing the stable association of MYC with target gene chromatin. This project combines drug discovery, structural biology, medicinal chemistry, biochemistry, and cutting-edge genomic approaches, along with powerful model systems, to identify, refine, and validate drug-like molecules that disrupt the MYC-WDR5 interaction, and to explore their effectiveness as anti-cancer agents against CRC. Within the five year funding period, we intend to produce first-in-class MYC?WDR5 inhibitors that will be fully validated for their utility in treating CRC and ready to proceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will address a clear unmet clinical need for targeted anti-MYC therapies, which are expected to have broad efficacy against CRCs for which there are only limited treatment options. Drugs discovered in this program will likely also have utility against a wide spectrum of cancer types.